Benzofuran-j-carboxylic acids
and esters



United States Patent Ofiice 3,235,566 Patented Feb. 15, 1966 The present invention relates to new benzofuran-3-carboxylic acids and more particularly to benzofuran-3-carboxylic acids which are substituted in 2- and S-position, and to a process of making and using same.

It is one object of the present invention to provide new and valuable benzofuran-3-carboxylic acids which are substituted in 2- and S-position and which have valuable pharmacological properties.

Another object of the present invention is to provide a simple and effective process of producing such new and valuable 2- and S-substituted benzofuran-3-carboxylic acids.

Still another object of the present invention is to provide valuable pharmaceutical compositions containing, as active ingredients such benzofuran-3-carboxylic acids which are substituted in 2- and S-position and which are useful muscle relaxants and central nervous system suppressing agents.

A further object of the present invention is to provide a method of treating humans and animals with such muscle relaxants and central nervous system suppressing agents.

Other objects of the features thereof will proceeds.

In principle the new and valuable substituted benzofuran-3-carboxylic acids according to the present invention are characterized by the following formula I group, the benzyl radical, or a substituted benzyl radical.

present invention and advantageous become apparent as the description (I) In said formula Compounds according to said Formula I are obtained by condensing p-quinone with a fl-keto carboxylic acid alkyl ester, preferably with a fl-keto carboxylic acid ethyl ester in the presence of an acid condensing agent. Anhydrous zinc chloride has proved to be the preferred condensing agent. The reaction is preferably carried out in an anhydrous lower alcohol such as anhydrous ethanol, at its boiling temperature. Likewise propanol, isopropanol, or isobutanol can be used, whereby the reaction is carried out at a temperature of 80-85 C.

The ,B-keto carboxylic acid alkyl esters, for instance, the ethyl ester used according to the present invention correspond to Formula II wherein R represents the same substituents as indicated hereinabove.

When proceeding according to said process, a benzofuran-3-carboxylic acid alkyl ester, substituted by a hydroxyl group in S-position, is obtained, which in addition thereto carries in 2-position the substituent R depending upon the ,B-keto carboxylic acid alkyl ester used as starting material as shown in Table 1. Thereafter, the resulting compounds are reacted with an alkyl halogenide of Formula III R Hal (III) wherein R represents the same substituents as indicated hereinabove.

This reaction is preferably carried out under alkaline conditions in a suitable polar solvent such as acetone or dimethyl formamide. When proceeding in this manner, the hydroxyl group in 5-position of the starting benzofuran-3- carboxylic acid alkyl ester is etherified without difiiculty and with a good yield. Preferably the alkyl bromides are used as alkyl halogenides because they are of satisfactory reactivity and readily available. Table 2 illustrates a number of possibilities of varying the substituent R in 5-position by using various alkyl halogenides and also the resulting benzofuran-3-carboxylic acid alkyl esters, etherified in 5-position and substituted in 2-position by substituent R The resulting benzofuran-3-carboxylic acid alkyl esters are finally saponified in a conventional manner, for instance, by means of alcoholic alkali metal hydroxide solution. The temperature during saponification may be between about 20" C. and the boiling point of the saponification mixture depending upon the nature and sensitivity of the various substituents. Sometimes it will be of advantage to carry out the saponification in the presence of an inert protective gas. The benzofuran-3-carboxylic acids according to the present invention are finally ob tained in a good yield by acidifying the clear saponifica tion mixture, for instance, by the addition of hydrochloric acid. A number of acids as they are obtained according to the present invention are given in Table 3.

The process according to this invention may be illustrated by the following equation:

The new compounds obtained according to the present invention possess valuable pharmacological properties. They are, for instance, excellent muscle relaxants and have a suppressing or inhibiting effect on the actions of the central nervous system.

The following examples serve to illustrate the present invention Without, however, limiting the same thereto.

3 EXAMPLE 1 Z-n-propyl-S-hydroxy benzfuran-3-carb0xylic TABLE 2 id th l ester Snbstituent R2111 Substituent R5 in Yield Melting 2- position 5-position (percent) point C 100 g. (0.575 mole) of n-butyroyl acetic acid ethyl ester 5 and 39.2 g. (0.228 mole) of anhydrous Zinc chloride are dissolved in 51.5 cc. of absolute ethanol. The solution is gg iP i lf i 2g 8 heated to 80-85 C. while stirring. 31 g. (0.288 mole) of DoI Be-HZ iQIIIIII 4 2 46-47 Do p-Bromo be yl... 76 60-01 p quinone are added thereto within 6 hours in portions Do" g f 59 5H9 each of 0.3 g. of said compound about every three minutes. Do m-Nitro benzyl. 50 121-122 After standing at a temperature of about C. for 12 10 BenzoylmethyL" 77 121422 Ethyl 1 Benzyl 90 39-40 hours, the preclpitate 1s filtered oil by suction from the n-Pro y1 d 85 51-53 black-brown colored solution and is subjected to frac- F 77-79 Is0butyl do 18 44- 16 tional recrystallization from acetic ac1d ethyl ester. About Plganylnn n do- 85 63-64 g. of the above mentioned ethyl ester are obtained, 94 90-91 p-Methoy le *1 Cl 1. 95 92-93 correspondmg to of the theoretical yield. Meltmg 15 p-Ethox; he ngi "d8 98 89-90 point: 105-106 C.

By proceeding as described hereinabove analogous 2- B.P., 11o-111/0.04 mm. Hg.

substituted S-hydroxy benzofuran-3-carboxylic acid ethyl esters are obtained by using the respective Z-Substituted fi-keto carboxylic acid ethyl esters as starting material. The resulting compounds are listed in the following Table 1.

TABLE 1 Substituent R2 in 2-position Meltg pgJ point Yield Z-methyl-S-benzyloxy benzofuran-fi-carboxylic acid ethyl ester 160 g. (0.727 mole) of 2-methyl-5-hydroxy benzofuran- -3-carboxylic acid ethyl ester are added to a suspension 2 B.P., 150/0.09 mm. Hg.

EXAMPLE 3 2-methyl-5-benzyloxy benzofuran-S-carb0xylic acid 60 g. (0.193 mole) of the ester prepared according to Example 2 are dissolved in a solution of 25 g. (0.45 mole) of potassium hydroxide in 200 cc. of ethanol, and cc. of water. The solution is heated to boiling under reflux for one hour, whereafter the alcohol is removed by vacuum distillation. The reaction inixtre is diluted with Water and the clear solution is acidified. The resulting precipitate is filtered off by suction, washed with dilute hydrochloric acid, and recrystallized from acetone. Colorless crystals of the melting point 2l7218 C. are obtained. The yield is 45.5 g., corresponding to 84% of the theoretical yield.

The following 2- and S-substituted benzofuran-3-carboxylic acids are prepared in an analogous manner by saponifying the corresponding 2- and S-substituted benzefuran-3-carboxylic acid ethyl esters, in which the substituents R and R represent the members indicated in of 276 g. (2 moles) of potasslum carbonate 111 1.2 l. of 40 Table 3.

TABLE 3 Substituent R Substituent Ra Yield Melting in 2-p osition in 5-p0siti0n (percent) 130016117, Remarks Methyl 2,3-prope-uyl 69 161-163 D n-Butyl 75 147-149 Benz 1 84 217-219 p-Bromo benzyl--. 83 203-205 At 20 C. for 12 hrs. m-Bromo benzyl. 94 202-205 Do. m-Nitro benzyl 205-206 Benzoyl methyl-" 55 1 179 At 20 C. under nitrogen for 3 weeks. Ethyl Benzyl 89 178-179 n-Propyl do 92 170-172 Cyclopropyl. 85 196-197 Isobutyl 90 189-191 Phenyl 83 196-198 p-Bromo phenyl" 89 254-256 p-Methoxy phony 86 217-218 p-Ethoxy phenyl 86 214-216 1 Decomposition.

etherified in 5-position, which carry in 2-position various isubstituents R can be prepared by proceeding in the same manner as described above by reacting the corresponding Z-substituted S-hydroxy benzofuran-3-carboxylic .acid ethyl esters with alkyl halogenides as indicated in the following Table 2..

The new compounds are preferably administered orally in the form of tablets, pills, powders, capsules, solutions, emulsions, suspensions, dispersions, and in any other suitable form. They are preferably not used as such, but are diluted with suitable diluting agents, thus, allowing better and more economical use to be made thereof.

In the case of powders, fine, uniform dispersion of the new compounds within the diluting agent is of importance. Such a fine dispersion can be achieved, for instance, by mixing and milling the new compounds with a solid, pulverulent extending agent to the desired fineness, or by impregnating the already milled, finely powdered, solid carrier with a solution of the active compound in a suitable solvent and then removing the solvent.

As solid carriers, which are suitable for the manufacture of useful pharmaceutical preparations, various inert pulverulent distributing agents as they are conventionally used in pharmaceutical compounding may be employed.

When preparing tablets, pills, powders, and the like, the commonly used diluting agents, binders, lubricants, and the like are added, such as sugar, lactose, talcum, starch, pectins; as binders gelatin, gum arabic, methyl cellulose, yeast extract, agar, tragacanth; and as lubricating agents, magnesium stearate, stearic acid, and others.

The new compounds may, of course, also be administered parenterally, for instance, by intravenous or intramuscular injection. For this purpose aqueous or saline solutions, especially of their Water soluble alkali metal salts or salts with suitable nontoxic organic amines or suspensions therein may be used.

Rectal application in the form of conventional suppositories is also possible.

Of course, many changes and variations in the starting materials, in the reaction conditions, temperature, duration, solvents used, in the methods of working up the reaction mixture and of purifying the benzofuran compounds and their alkali metal salts, and the like may be made by those skilled in the art in accordance With the principles set forth herein and in the claims annexed hereto.

We claim:

1. 2-methyl-5-benzyloxy benzofuran-3-carboxylic acid.

2. 2-methyl-5-benzyloxy benzofuran-3-carboxylic acid ethyl ester.

3. 2-lower alkyl-S-benzyloxy benZofuran-3-carboxylic acid.

4. 2-10Wer alkyl-S-benzyloxy benzofuran-3-carboxylic acid ethyl ester.

5. Z-cyclopropyl-S-benzy1oxy benzofuran-3-carboxylic acid.

6. The S-benzyloxy benzofuran-3-carboxylic acid having in 2-position a substituent selected from the group consisting of phenyl, lower alkoxy-substituted phenyl, and halogen-substituted phenyl.

7. 2-ethyl-5-benzyloxy benzofuran-3-carboxylic acid.

8. 2-n-propyl-5-benzy1oxy benzofuran 3 carboxylic acid.

9. 2-isobutyl-5-benzyloxy benzofuran-3-carboxylic acid.

10. 2-methyl-5-allyloxy benzofuran-S-carboxylic acid.

References Cited by the Examiner UNITED STATES PATENTS 5/1956 Goodman 167-65 2/1957 Phillips et a1 16765 OTHER REFERENCES NICHOLAS S. RIZZO, Primary Examiner. 

3. 2-LOWER ALKYL-5-BENZYLOXY BENZOFURAN-3-CARBOXYLIC ACID.
 6. THE 5-BENZYLOXY BENZOFURAN-3-CARBOXYLIC ACID HAVING IN 2-POSITION A SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF PHENYL, LOWER ALKOXY-SUBSTITUTED PHENYL, AND HALOGEN-SUBSTITUTED PHENYL. 